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152 Cards in this Set

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Hemostasis:
physiological healthy mechanism to stop bloodloss and keep it liquid.
Thrombosis:
pathological formation of bloodclots
Hemorrhage:
pathological bleeding and inability to form blood clots
8 components of hemostasis:
-Vascular wall
-Vascular endothelium
-Platelets
-Fibrinogen
-Clotting factors
-Calcium
-Fibrinolytic enzymes
-Regulatory factors
Components of primary hemostasis:
-Platelets
-Vasoconstriction
Components of secondary hemostasis:
-Clotting factors
-Fibrin
3 Main Processes that occur during primary hemostasis:
platelet
-Adhesion
-Activation
-Aggregation
Why the vasoconstriction in primary hemostasis?
To minimize bloodloss at penetrating injury sites.
Purpose of secondary hemostasis:
Fibrin formation to stabilize the platelet clot
Which stage takes longer?
Secondary
What is wound healing?
The process of clot remodeling and removal in the days and weeks following injury.
3 Processes involved in wound healing:
-Fibrinolysis
-Angiogenesis
-Tissue remodeling
Where are platelets produced?
-Bone marrow
-Spleen
What are platelets produced from?
Polyploid progenitor megakaryocyte
How are platelets born?
By megakaryocyte fragmentation
What does polyploid mean?
64N
Platelet structure features:
-No nucleus
-Actin contractile elements
-Large surface area
-Organelles
3 types of granules in platelets:
-Alpha
-Dense
-Lysosomes
What 5 proteins are stored in platelet alpha granules?
-vWF
-factor V
-Fibrinogen
-P-selectin
-PDGf
What do platelets biosynthesize?
From what?
TxA2 from Arachidonic acid
What are 3 stored metabolites in dense granules?
-ADP
-Calcium
-Serotonin
When do platelets release their granules?
When activated
4 things that platelets have receptors for:
1. Adhesion
2. Thrombin
3. ADP
4. TxA2
What is the plt receptor for fibrinogen?
GPIIb-IIIa
What is required for the plt fibrinogen receptor to be active?
Activation by the binding of Thrombin, ADP, or TxA2
How do platelets activate to adhere?
By spreading out by their actin filaments
What allows platelets to detect the appropriate site for adherence during primary clotting?
vWF - found on the collagen of the vascular wall underlying the endothelium
What is the platelet receptor for vWF factor?
GP1b-a
How does vWF get onto the vascular wall?
Circulating vWF binds to it; this ccauses a conformational change so it can interact with its platelet receptor.
What happens to platelets when they bind vWF via their GPIb-a receptor?
They undergo shape change (actin) and release stored mediators in their granules.
What is the result of platelets releasing stored mediators like ADP?
Attraction and activation of more platelets.
2 most important mediators for aggregation released by activated / shape-changed platelets on injury site:
-ADP
-TxA2
What happens when platelets release ADP and TxA2?
It calls additional platelets to adhere to the initial clot.
What happens after platelets are adhered, activated, and aggregated?
Their Fibrinogen GPIIbIIIa receptor has been activated so it can bind to fibrinogen swimming in the blood.
What is achieved by fibrinogen binding?
It links together many MORE platelets (glue) and leads to aggregation - achieves formation of primary platelet clot.
How stable is the primary clot?
Not very stable
How is the clot stabilized?
By activation of the coagulation cascade - the endproduct being Thrombin which modifies the crosslinking of platelets by converting fibrinogen to fibrin.
What exactly does Thrombin do to soluble Fibrinogen?
Cleaves 2 AA from its N-terminal
What is the result of cleaving fibrinopeptides A/B from Fibrinogen monomer?
It generates sticky fibrin monomers that spontaneously POLYMERIZE to generate a huge aggregate - stabilizes clot.
What molecule is essential for crosslinking of fibrinogen polymers?
Factor 13
What exactly is the function of factor 13?
Irreversible crosslinking of fibrin polymers by covalently binding them together.
How do you know there is enough fibrinogen available for clotting?
It is the most abundant protein in plasma after albumin.
What activates factor 13?
Thrombin (same thing that converts fibrinogen into fibrin monomers).
What disease is associated with lack of GPIIb-IIIa? What is this receptor again?
Glanzmann's thrombasthenia - this is the fibrinogen receptor.
What is the GP1b-a receptor? What disease is associated with it?
vWF-receptor; mutation causes Bernard Soulier syndrome
What mutation causes von Willebrand disease?
vWF mutation
Where are coag factors found? In what state?
Circulating in blood as inactive proenzymes
What is essential for coag factors to function?
Activation by enzymatic proteases
What is the endproduct of the coag cascade?
Activation of Prothrombin into Thrombin.
2 Main functions of Thrombin:
-Cleaves fibrinogen into fibrin
-Activates Platelets
Where are most coag factors made?
In the liver
Exceptions to liver synthesis:
-Factor V (liver/megakaryos)
-vWF (endothelium/megakaryos)
-Tissue factor (not endothelium)
What are the vit K dependent factors?
2,7,9,10, Proteins S and C
Which coag factors are cofactors?
5, 8, Ca, Phospholipid, TF, and Protein S
Which coag factors are the most abundant and highest in concentration?
-Fibrinogen
-Thrombin
Which coag factor acts as a chaperon for Fx VIII?
vWF!
How are vit K dependent and independent coag factors different?
Based on the AA sequence that consists of their active site.
But they look structurally similar.
What is the reactive site used by VitK dependent factors?
AGY
What is the reactive site used by VitK independent factors?
TCN
What is VitK dependence?
Posttranslational carboxylation and addition of glutamic acids to the Gla of VitK dependent Fxs
What is the result of carboxylation of glutamic acid residues of Vit K dependent coag factors?
They become sensitive to calcium.
Where is the source/function of calcium here?
Released locally from activated platelets - allows the factors to assemble into little machines to generate thrombin.
What blocks the vit-K dependent carboxylation of the factors?
Warfarin
What is necessary for coag factors to be active? What does activation result in?
Limited proteolysis; results in release of the business end Catalytic Serin Protease domain.
what initiates the coagulation reactions (extr/intr)?
Extrinsic: tissue factor/VII
Intrinsic: surface type in vitro
What processes happen after initiation of the coag reaction?
-Amplification mediated by platelets and thromin
-Termination via an endogenous anticoagulant mechanism.
What is the purpose of terminating the coagulation reaction?
To limit the clot to the site of injury.
Why is the intrinsic pathway called that?
Intrinsic mechanism of clotting - platelets will just clot when contacting a surface.
What are TENase and PROTHROMBINase?
The 2 important 'machines' in the common pathway that generate massive amts of thrombin.
What does TENase consist of?
-9a/8a
-platelet cofactors
-calcium
What does Prothrombinase consist of?
-Xa/Va
-platelet cofactors
-calcium
What initiates coagulation?
Tissue Factor
Where is Tissue factor? How does it activate coagulation?
Membrane bound on muscles - sticks out and when injured binds and activates Fx VII
What does Fx 7a do?
-Activates Fx 9
-Activates Fx 10
What does factor Xa do?
Activates a LITTLE BIT of thrombin from prothrombin - not by the action of machines.
What happens after Xa is made and what makes it happen?
Propagation and amplification - done by Thrombin itself - the little bit initially formed.
What is involved in propagation and amplification?
Thrombin activates the other cofactors to assemble the enzyme machines Tenase and Prothrombinase - these make LOTS of thrombin.
What type of feedback allows propagation and amplification?
Positive
4 Mechanisms by which the coagulation reaction is LIMITED:
1. Localization of enzyme generation
2. Specific destruction of cofactors/activated cofactors
3. Plasma protease inhibitors
4. Bloodflow
How does enzyme generation localization help limit coagulation?
Because assembly of the enzyme machines occurs only at sites of injury via interaction w/ platelets - floating molecules are less active.
What molecules achieve specific destruction of factors and cofactors to limit coagulation?
-Thrombomodulin
-Protein C
What are 2 ways by which normal non-injured endothelial cells limit and stop coagulation?
1. By inhibiting plt activation
2. By inhibiting coagulation activation
3 inhibitors of platelet activation produced by normal non-injured endothelial cells:
-Nitric oxide
-Ecto-ADPase
-Prostaglandin I2
What are the plasma protease inhibitors? (3)
1. AT III / Heparin
2. Heparin cofactor II
3. Tissue Factor Pathway inhibitor
How does bloodflow limit coagulation?
-Removes/dilutes activated factors
-Hepatic clearance
What is the essential requirement for AT3 to work?
NORMAL Endothelium - it has HEPARANSULPHAT proteins with LOTS of sugar residues attached
What is the function of the proteoglycans on endothelium in the AT3 mechanism?
Sugars lure in Thrombin and change its conformation when it binds so that Thrombin then lures in Antithrombin.
How does AT3 behave when lured in by Thrombin bound to heparansulphat?
As a suicide bomber; binding Thrombin forms an irreversible TAT complex and molecular destruction ensues.
What does AT3 do after forming the TAT complex with thrombin?
AT3 turns thrombin inside out.
How is it that AT3 which is constantly present in the blood, doesn't inhibit clotting and thrombin constantly?
It requires the polysaccharides on normal endothelium; if it's damaged, it won't inhibit it.
How do heparan-like drugs work?
By facilitating the formation of TAT complexes in hypercoagulable states - inhibit coagulation.
What is thrombomodulin?
A molecule that modulates Thrombin; bound to normal uninjured endothelium
What is thrombomodulin situated next to on the endothelial membrane?
Protein C receptor
What binds the Protein C receptor?
Protein C - it is Vit K dependent and always circulating and bound to uninjured endothelium, but inactive.
How does Thrombomodulin function?
1. Thrombomodulin binds Thrombin
2. Complex activates Protein C
3. Results in APC
What does APC do? What type of molecule is it?
A protease - floats off, binds Protein S and inactivates Fx 8a and 5a -> destroys the enzymatic machines that make Thrombin.
What do we call the action of Thrombomodulin?
Natural anticoagulation
When does Thrombomodulin and Protein C anticoagulation occur?
Constantly
What diseases affect the Thrombomodulin pathway?
-Protein C deficiency
-Protein S deficiency
What results from ProteinC/S deficiency?
Porphyra purpura fulminans - many small bruises on infants just after birth due to widespread activation of coagulation.
What happens if you don't have the APC/Thrombomodulin pathway?
(term for it)
The whole body clots itself to death - Thrombophilia
What is the most common abnormality related to the Thrombomodulin/protein c pathway?
Factor V Leiden
What is Factor V Leiden?
Mutation of Factor V so that it resists APC and is not cleaved by it.
Result of FVLeiden:
High risk of thrombosis
How many people have the Factor V Leiden mutation?
1/20
Why is the Fx V Leiden mutation so prominent in the population?
Because having it protects you from sepsis.
Why does the FVLeiden mutation protect against sepsis?
It binds bacteria if they get into blood and aggregates them, making the clump more susceptible to macrophages.
Most common genetic trait that predisposes patients to thrombosis:
Fx V Leiden
How is a clot removed?
Fibrinolysis
What molecule achieves fibrinolysis?
Plasmin
What does Plasmin do to fibrin?
Chops it up into little pieces called D-dimers
D-dimer is an indication of:
How active the fibrinolysis process is
What is the fibrinolysis pathway similar to?
Coagulation
What is the most important inhibitor of fibrinolysis?
PAI-1 -> plasminogen activator inhibitor
5 Primary bleeding disorders:
-Glanzmann's thrombasthenia
-Bernard Soulier
-vWD
-Hemophilia A
-Hemophilia B
Glanzmann's Thrombasthenia
GPIIBIIIa - fibrinogen receptor on platelets mutated

2,3,F,G
Bernard Soulier Syndrome
-symptom
GPIb-a - vWF receptor on platelets defective
Symptom: giant platelets
von Willebrand disease
problem with vWF - also will see problems with Fx VIII because it's the chaperone
Hemophilia A
Fx 8 deficiency
Hemophilia B
Fx 9 deficiency
3 types of Secondary bleeding disorders
-Vit K deficiency
-Liver disease
-Thrombocytopenia
How are bleeding disorders treated?
With replacement therapy of plasma or pure factors
What type of tube do you collect blood for PT or PTT? Why?
Citrate - to remove the calcium and prevent activation.
What measures the common pathway?
Protime
What does the PTT measure?
Intrinsic and Extrinsic factors
What ingredients do you add for the PT?
-Phospholipid
-Ca
-Tissue factor (thromboplastin)
What ingredients do you add for the PTT?
-Kaolin (surface)
-Phospholipid
-Calcium
What is the TcT (Thrombin clotting time) used to test?
How well your fibrinogen is functioning.
What do you add to run the TT?
-Lots of Thrombin
-Calcium
How are the PT and PTT expressed?
INR - international normalized ratio
3 Drug strategies for treating hemostasis problems:
-Anticoagulants
-Antiplatelets
-Fibrinolytics
3 types of anticoagulant drugs:
-Coumadin
-Heparin
-Hirudin
What does Coumadin do?
Inhibits gamma-carboxylation of Vit-K dependent factors
What does Heparin do?
Enhances AT3 action (mimics heparansulphat proteoglycans)
What is hirudin?
Similar to AT3; inhibits the TAT complex.
What is the #1 most common genetic cause of hypercoagulation?
Fx V Leiden mutation - APC resistance
What is the #2 most common cause of hypercoagulation?
Increased Prothrombin levels
What is more common, primary or secondary causes of hypercoagulation?
Secondary
Common types of secondary causes of hypercoagulative states:
-Cancer
-Pregnancy
-Diabetes mellitus
-Sepsis
-Stasis
-Obesity
Why is pregnancy associated with hypercoagubility?
Because as the body prepares for massive trauma and bleeding it ramps up its coagulative mechanisms.
Why is sepsis associated with hypercoagubility?
Because bacteria induce clotting
Why is obesity associated with hypercoagubility?
Because fat cells produce PAI-1 which is an inhibitor of plasmin so reduces the natural anticoagulative pathway.
If a patient shows up with massive clotting and has no other symptoms or predisposing factors what would you suspect?
Cancer
Why is inflammation associated with hypercoagubility?
Because it causes tissue factor to be expressed on endothelial cells, which otherwise do NOT express it normally.
How is platelet function tested?
By aggregation studies
What agonist detects vWF function?
Ristocetin
4 agonists used to test platelet function:
-ADP
-Epinephrine
-Collagen
-Ristocetin
3 Types of Antiplatelet drugs:
1. Fibrinogen receptor blockers
2. Thromboxane synthesis inhibitors
3. ADP receptor blockers
What receptor is blocked when blocking the fibrinogen receptor? Example of one of these drugs:
GPIIbIIIa
Example: RGD mimetics
What are 3 TxA2 synthesis inhibitors?
-Cox inhibitors -> ASPIRIN or INDOMETHACIN
-Phospholipase inhibitors -> STEROIDS
What are 2 clotbusters?
-TPA
-Streptokinase
What do TPA and Streptokinase do?
Activate Plasminogen